Pre-transplant myeloid dendritic cell deficiency associated with cytomegalovirus infection and death after kidney transplantation.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells critical for immunity. We previously demonstrated a significant association between pre-transplant blood myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) deficiency and post-transplant BK viremia in renal transplant recipients. In the current post-hoc analysis, we studied the association of these same pre-transplant DC levels with other post-transplant outcomes. METHODS: Pre-transplant peripheral blood mDC and pDC levels were quantified using flow cytometry in 78 patients undergoing kidney transplantation. Post-transplant outcomes were analyzed, including infection, rejection, and patient death, with a median follow-up of 5.3 years. Associations between DC levels and outcomes were assessed using logistic regression analysis and Cox proportional hazards models. RESULTS: An independent association of mDC levels with post-transplant cytomegalovirus infection (adjusted odds ratio 7.0, P = 0.01) and patient death (adjusted hazard ratio 13.0, P = 0.015) was found. No associations were demonstrated between levels of either DC subtype and bacterial infections or rejection. CONCLUSIONS: Pre-transplant mDC deficiency is significantly associated with CMV infection and death after kidney transplantation.

Preemptive retransplantation for BK virus nephropathy: successful outcome despite active viremia.

BK virus nephropathy (BKVN) is now recognized as a major cause of renal allograft loss. Recent reports suggest that retransplantation in patients with graft loss due to BKVN is safe after return to dialysis. Since early transplantation is associated with improved outcomes, it would be advantageous if this procedure could be performed prior to ultimate graft loss. However, little data are available regarding the safety of this approach during active viremia. In this report, we describe successful preemptive retransplantation with simultaneous allograft nephrectomy in two patients with active BKVN and viremia at the time of surgery. With 21- and 12-month follow-up, respectively, both patients have stable allograft function and no evidence for active viral replication. We conclude that preemptive retransplantation can be considered in patients with failing allografts due to BKVN.

The effects of renal transplantation on circulating precursor dendritic cells.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells that induce and regulate immune responses. Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid DC populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. METHODS: Using flow cytometry, PBDC levels were quantified in patients with end-stage renal disease (ESRD) undergoing renal transplantation. RESULTS: PBDC levels were significantly reduced in ESRD patients pretransplantation compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving antilymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pretransplant values concurrent with overall reduction of immunosuppression. Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall immunosuppression. CONCLUSIONS: Our findings suggest that PBDC levels may reflect the degree of immunosuppression in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss, and infectious complications.

What happens to renal transplant recipients who lose their grafts?

Little attention has been given to the fate of patients who lose their grafts. We reviewed outcomes of 438 recipients of first renal allografts who underwent transplantation at our institution between January 1, 1988, and December 31, 1997, and lost their grafts or died with a functioning transplant. Of the 438 patients, 168 patients died with a functioning transplant. The most common causes of death were cardiac disease, infection, and cancer. Patients who died with a functioning graft were older (>49 years, 64.3%) than patients who died after returning to dialysis therapy or who are still alive (>49 years, 25.9%). Eighty-six patients (39%) who returned to dialysis therapy were again placed on a cadaveric waiting list. Only 44 patients received a second transplant, of which 30 transplants (68.2%) are still functioning. Our study shows that relatively few patients who lose kidney transplants are returned to the cadaveric waiting list and even fewer undergo retransplantation.

Outcome of kidney transplants in patients known to be flow cytometry crossmatch positive.

BACKGROUND: The clinical significance of the flow cytometry crossmatch has been addressed in several retrospective studies, but the results have been controversial. There are no prospective studies in which patients known to be antibody positive underwent transplantation. METHODS: The flow cytometry crossmatch was performed prospectively in 1130 renal transplant recipients. A decision to perform transplantation was based on whether the positive results were on T or B cells, in the current or peak specimen, and taking into account the presence or absence of other immunological risk factors. One hundred antibody-positive patients received a transplant. Graft survival and rejection episodes were analyzed in this group and compared with 100 crossmatch-negative patients matched for age, sex, race, and time of transplantation. RESULTS: The incidence of rejection at 1 month was higher in antibody-positive patients (26%) than in antibody-negative patients (12%, P<0.01). Early rejection seemed to be more frequent in antibody-positive patients regardless of whether the antibodies were current or historic, or against T or B cells. There were more steroid-resistant rejections in antibody-positive than in antibody-negative patients. However, biopsy specimens showed that vascular lesions that can be associated with humoral rejection were not more frequent in the antibody-positive patients than in the controls. There were no differences in graft survival between the two groups. CONCLUSIONS: Low-level preformed alloantibodies detected by flow cytometry represent a risk of rejection even for patients purposely selected for having no additional immunological risk factors. The risk seems to be due to donor-specific memory rather than to a direct effect of the antibodies. The results indicate that flow cytometry provides useful information to assess donor-recipient compatibility.

Delayed graft function after renal transplantation.

BACKGROUND: There is a strong association between delayed graft function (DGF) and reduced graft survival (GS) of cadaveric renal transplants. This study was performed to identify donor characteristics that might predict adverse outcomes. METHODS: We reviewed the folders of 509 consecutive organ donors for 586 renal transplant recipients receiving grafts between 1990 and 1995. A uniform immunosuppression protocol was employed. RESULTS: The factors that did not alter the rate of DGF were procurement year, local versus shared organs, donor gender, race, hypotension, serum creatinine level and trend, blood transfusions, and vasopressor use and dose. The factors that did alter the frequency of DGF were cause of death (P=0.0053), donor age (P=0.0017), cold ischemic time (P=0.0009), anastomotic time (P=0.0012), combined cold ischemic time and anastomotic time (P=0.00018), and body mass index (P=0.009). All of the factors with the exception of body mass index were of comparable import when analyzed by multiple logistic regression. One-year GS of patients without DGF was 93.2%, and the GS of those with DGF was 76.6% (P < 0.0001). However, none of the donor factors correlated with 1-year GS. Seventy-seven donors were the source of paired transplants performed by our program. Sixty percent were concordant for immediate function, 32% were discordant for DGF with equal numbers affecting the first or second graft, and in only 8% did DGF affect both grafts. CONCLUSIONS: Donor factors associated with DGF were increased ischemia, donor age, and cause of death. Although there is a close association between DGF and reduced GS, there is no association between these donor factors and GS. This seeming paradox suggests that unknown variables contribute heavily to early graft outcome.

Hypomagnesemia in renal transplant patients: improvement over time and association with hypertension and cyclosporine levels.

Hypomagenesemia is frequently encountered early after kidney transplantation, especially in patients receiving cyclosporine (CsA). However, there have been no studies addressing the natural history of this disorder in adult transplant recipients. We conducted this investigation to study the change in the prevalence of hypomagnesemia over time in renal transplant patients as well as to determine the factors associated with this change. Three patient groups were studied: 24 CsA-treated patients followed longitudinally at 1, 3 and 6 months post-transplant (Group 1a, 1b, 1c); 33 CsA-treated patients at least 2 years post-transplant (Group 2; mean follow-up 55 +/- 25 months); and 31 non-CsA-treated patients at least 2 years post-transplant (Group 3; mean follow-up 132 +/- 57 months). The following parameters were monitored: serum and urine magnesium levels; serum potassium; creatinine clearance; fractional excretion of magnesium; and trough CsA levels. In group 1 patients, longitudinal follow-up showed a significant linear trend for improvement in the serum magnesium over time (1.6 +/- 0.3, 1.7 +/- 0.2, 1.8 +/- 0.2 mg/dl; p = 0.0015) as well as a decline in the whole blood CsA level (316 +/- 103, 251 +/- 82, 194 +/- 67 ng/ml; p = 0.0015) at 1, 3 and 6 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A preliminary report of diltiazem and ketoconazole. Their cyclosporine-sparing effect and impact on transplant outcome.

A prospective randomized trial was conducted to compare the effect of diltiazem (DILT) with ketoconazole (KETO) on sparing of cyclosporine dose and renal transplant outcome. Renal allograft recipients 18 years old and older were eligible for the study. Triple immunosuppression (TRIPLE) including prednisone, azathioprine, and CsA was administered to all patients. The maintenance CsA dose varied by study group. Patients were randomized to receive one of three treatment strategies: group 1-TRIPLE (CsA 8 mg/kg/day); group 2--TRIPLE (CsA 6 mg/kg/day) + DILT (60 mg b.i.d.); group 3--TRIPLE (CsA 3 mg/kg/day) + KETO (200 mg/day). Modification of the DILT dose was allowed as needed to effect blood pressure control in group 2 patients. Mean 1-month CsA dose reductions were 30% and 60% of controls in group 2 and 3, respectively. A continued effect over time was observed in patients administered KETO but not DILT. At 1 year patients taking KETO required an average of 77% less CsA than the average dose necessary to effect similar parent CsA blood levels when no enzyme inhibitor was used. The use of KETO and DILT for 1 year allowed for 53% and 14% reductions in CsA cost, respectively. These savings include the cost of the KETO or DILT. Serum creatinines, mean arterial pressure (MAP), and incidence of liver function abnormalities were similar throughout treatment groups. The rate of rejection, time to rejection onset, and survival (GS/PS) were not different among the groups. Fungal infections were fewer in patients treated with KETO (12%) than in controls (16%) and patients randomized to DILT (19%). KETO failed to prevent Aspergillus infection in one individual. The investigation failed to identify any harmful result of treating renal allograft recipients with either DILT or KETO for the purpose of reducing CsA expense.

Immunosuppression without prophylactic antilymphocyte preparations.

1. Triple-drug immunosuppression following third party transfusion can result in graft survival equal to protocols that employ prophylactic antilymphocyte preparations. 2. T1/2 was statistically improved in cadaveric and living-related donor grafts in the CsA era. 3. Patients 65 years and older had an excessive death rate. Younger groups were admixed. Extreme youth was not a risk factor. 4. Black recipients had excessive late graft loss. 5. Diabetic recipients had only a slight decline in graft and patient survival rates. 6. First and multiple graft recipients had similar transplant survival rates. 7. Delayed graft function remains costly in this immunosuppressive scheme.

Renal transplantation: a 20-year experience at the University of Florida.

Substantial gains have been made in both patient and graft survival during 20 years of transplanting kidneys at the University of Florida. The number of transplant recipients yearly has increased from six in 1966 to more than 100 in 1986. The use of immunosuppression reflects our evolving understanding of transplant immunology, with current morbidity and mortality rates considerably improved over those of the early years. This paper summarizes our transplantation experience over the past two decades.

Incidental and purposeful random donor blood transfusion. Sensitization and transplantation.

We conducted a prospective study to gauge the frequency and degree of sensitization by transfusion and/or pregnancy in 797 candidates for first renal transplants. Sensitization was proportional to the number of blood transfusions. Multiple transfusions or a history of pregnancy without transfusions had similar effects on sensitization. The combination of transfusion and prior pregnancy resulted in sensitization of 1/3 of the candidates. Patients who were not sensitized and were accepted for 1-haplotype living-related donor grafts or first-cadaver donor grafts were transfused to receive a total of 5 units of packed red blood cells. Parous patients had an undue rate of antibody formation and alternate means of selecting and managing parous women are described. Nonparous candidates had a low rate of sensitization (8%) that did not prove an impediment to obtaining a transplant. Only 2% of prospective LRD graft recipients developed antibody against their intended donor. Transplant patients were generally managed with azathioprine and prednisone. One-haplotype LRD graft survival of protocol patients was 93.7% one year posttransplant, and 82.1% at 5 years. One-year CD graft survival was 77%. There was no reduction in graft survival when the interval between transfusion and transplantation exceeded one year. Random donor transfusion is effective in improving renal graft survival. Some recent multiinstitutional reports indicate a reduction or absence of the transfusion effect with current immunosuppression. Discarding blood transfusion as a preparation for transplantation may be ill-advised pending a prospective study.

Late results of renal transplantation.

A total of 315 (64%) of 491 primary cadaver and living-related donor transplants performed from 1975 through 1984 were still functioning at 24 months. These selected patients were examined further to assess the impact of several risk factors on late graft and patient survival. Black recipients, patients with underlying diabetes mellitus or hypertension, patients with poor renal function at 24 months, and recipients of cadaver grafts had significantly poorer long-term graft survival. Age greater than or equal to 40, diabetes or hypertension, poor 24-month function, and cadaver donor transplantation were associated with poorer long-term patient survival. Considerable improvement in graft survival at 24 months was seen in 1980-1984 compared with the earlier period, coincident with our adoption of routine pretransplant random donor blood transfusion. In contrast, long-term graft survival in patients with functioning graft at two years did not improve significantly over the same period. Although living-related donor transplants showed greater graft and patient survival than cadaver donor grafts by univariate analysis, no such advantage was demonstrated by multivariate analysis.